Conceptual basis for active surveillance

1. Screening results in overdiagnosis2. Clinically insignificant disease can be identified3. All treatments have significant side effects and

cost. 4. Delayed radical treatment is still curative. 5. The psychological burden is acceptable (less

than the effects of overtreatment).

The Screening Problem: U.S. ExampleWelch JNCI 2005:97:1132-7

Biopsy of all men with PSA > 2.5:Result in 775,000 diagnosed cases,

3 x higher than current incidence

This is 25 times the 30,350 Prostate Cancer deaths per year in the US!

PSA testing in US men

75% of men and 87% of male MDs have had a PSA50% tested regularlyLifetime risk of diagnosis 19% (from 10% in pre PSA era)>90% treated radically

Overtreatment is common

Studies of non-screen detected men

AlbertsenJohannsonSPCGS-4

PSA era studiesCancer registriesPCPTESRPC

20-Year Outcomes Following Conservative Management of Clinically Localized Prostate CancerAlbertsen P et al, JAMA. 2005;293:2095-2101

Lead Time effect 0 10 20 30 Years 0 10 20 25

Gleason score shift102030

ESRPC: % of indolent cancer at surgery

PSA 1st screen 2nd screen

<3 67 563-4 45 31

4-10 27 46

>10 13 36Total 33 43

Estimates of overdiagnosis: Draisma 2007

T1 69%

T2 38%

T3 30%

Gleason < 7 62%

7 40%

>7 8%

Candidates for active surveillance

60% of new cases are Gleason 5-6 (CapSure) 80% PSA ≤ 1065% T1c, 25% T2aThus 45-50% of newly diagnosed cases are favorable riskAbout 50% of these fulfill criteria for insignificant prostate cancerOne third of patients (85,000/year in US and Canada)

The three challenges of surveillance

Identifying the right patientCommunicating safety (‘cancer hysteria’)Trigger for intervention

Timely treatment for patients reclassified as high riskAvoid jumping the gun

Surveillance therapy with selective delayed intervention

Favorable risk (D’Amico):Gleason ≤ 6PSA ≤ 10T1c/T2a

In younger patients≤ 1/3 cores positive< 50% involvement of all cores

If available, PSA DT > 3 years or PSA velocity < 2.0 ng/ml/yearHypothesis:

Most can be observedDelayed treatment effective in those whose disease appears to be higher risk over time

‘Animals in the barnyard’ and cancer natural history

Only the rabbits benefit from early diagnosis and treatment.

Identifying the rabbits: the controversies

PSA kineticsReliability (? too late)Interpretation (Velocity vs doubling time)How to calculate

BiopsyHow often, how many coresTrigger for intervention: extent/volume/grade shift

Identifying the rabbits: Toronto approach

Rapid PSA doubling timePSA every 3 months x 2 years then every 6 months

Usually decision to intervene at 2 years, 8-9 PSAsPSA DT < 3 years (20% of patients)

Gleason grade progressionBiopsy at 1 year (confirmatory)Then every 4 years (progression)Treat if Gleason 4+3 or worse (5% of patients)

Unequivocal clinical progression to T3 (3%)Guidelines, not rules

Distribution of PSA doubling times in 331 patients on surveillance. Choo, Klotz J Urol 2002

0

5

10

15

20

25

<1 2 3 4 5 6 7 8 9 10 10-15 20 30 40 50 100 >100PSA Doubling time

Median%

Overall and disease specific survival in Toronto surveillance cohort (adapted from Klotz L, J Clin Oncol. 2005 Nov 10;23(32):8165-9)

Overall Survival (n = 331)

Time (years)

Surv

ival

dis

tribu

tion

func

tion

(100

%)

0 1 2 3 4 5 6 7 8 9 10

0.0

0.2

0.4

0.6

0.8

1.0

Low risk of progressionHigh risk of progression

Cause Specific Survival (n = 331)

Time (years)

Sur

viva

l dis

tribu

tion

func

tion

(100

%)

0 1 2 3 4 5 6 7 8 9 100.

00.

20.

40.

60.

81.

0

Low risk of progressionHigh risk of progression

P=0.51 P=0.05

The problem of calculating PSA DT

FLO: First and last months observationBLF: Best line fit

General Linear Mixed Modeling

Allows for individual predictors of intercept and slope to be integrated into model

Aggregate estimate of variation used to reduce effect of individual PSA variation on PSA DT calculation

For high risk line: ln(PSA) = 1.003 × ln(baseline PSA) + 0.112 × time + 0.041 × time2

For low risk line: ln(PSA) = 1.03 × ln(baseline PSA) – 0.0056 × Age + 0.046 ×Gleason + 0.081 × time + 0.0038 × time2

Zhang L, Loblaw DA, Klotz L. J Urol 2006

Time (years)

PS

A (n

g/m

l)

0 1 2 3 4 5

0

5

10

15

20 High risk

Low risk

A

Time (years)

PS

A (n

g/m

l)

0 1 2 3 4 5

0

5

10

15

20

High risk

Low risk

B

Time (years)

PS

A (n

g/m

l)

0 1 2 3 4 5

0

5

10

15

20High risk

Low risk

C

High risk—Intervene Intermediate: continue close follow up

Low risk: relax follow up

GLMM approach toPSA DT during active surveillance

www.psakinetics/sunnybrook.ca

http://psakinetics.sunnybrook.ca

Effect of PSA triggers on stable patient cohort

General linear mixed model of ln(PSA) 0%PSA threshold > 10 15%

Linear regression of ln(PSA) vs time < 2yr 39%

Ln(PSA) vs time < 2 years using first and last PSA

29%

Actual PSA velocity > 2.0 49%

Calculated PSA velocity > 2.0 49%

PSA DT and surveillance:Khatam A, Hugusson Int J Cancer 120, 170-174 (2006)

270 active surveillance (from Swedish arm of ESRCP) 39% treated70 RPs⌧9 (12%) PSA relapse⌧80% of these had PSA DT < 2 years⌧0/37 with PSA DT > 4 years relapsed

14 deaths (5%); 0 from PCa⌧No metastatic progression

Williams SK, Soloway M AUA 2007 Ab 1410

175 favorable risk patients managed with ‘Toronto’approach99 with > 1 yr f/u, median 4 yrsMean age 66Mean PSA 5.7Intervention 8%: 2 RP, 3 XRT, 3 ADTMean PSA DT

Untreated 13.1 yrsTreated 3.6 yrs

5 year PFS 85%PCa survival 100%

Modelling the risk: A number needed to treat analysis

The Scandinavian trial

Mortality reduction at 10 years

NNT

Bill-Axelson2005

All 5% 20

Holmberg2006

<65 11% 9

65 0.3% >300

A 50% risk reduction may yield little clinical benefit

Clinically insignificantDisease

Cured by therapy

Death from disease

Swedish cohort differed from patients diagnosed in 2006

Mean age 64.7Mean PSA 12.85% screen detected75% T240% Gleason 7 or higher

Mean age 62Mean PSA 695% screen detected70% T1c60% Gleason ≤ 6Volume migration

Swedish trialTypical screen diagnosed patient

Unanswered question:

NNT forLow gradeSmall volumeScreen detectedOption of selective delayed therapy

NNT for each cancer death avoided at 20 years for favorable risk prostate cancer: RP vs surveillance

Swedish trial Swedish trial Corrected for 10 years 20 years (estimate) grade difference

Include salvage opportunity 80

20 50

Lead time in screenedpopulation 20 years

20 9

Predicted survival - conservative management of screen-detected prostate cancer

Parker et al. BJC (2006) 1361-8

Why Men Don’t Want to Wait

Cancer Hysteria: Who benefits?

Fundraising Cancer SocietiesCancer Research organizationsPhysiciansResearchersOther health care workers in the cancer fieldMediaEnvironmental activists

Who is Disadvantaged by Cancer Hysteria?

The patient

Fear is a Danger to Your Health

‘Cancer’ and sense of doom“The dread expands and solidifies into such a major obstacle that I simply can’t get past it.”

Patients may feel so hopeless that they can’t absorb the medical facts

“The first step in positive thinking is to be able to understand what’s actually going on. Positive thinking begins with clear thinking.”

- a Patient

“The first step in positive thinking is to be able to understand what’s actually going on. Positive thinking begins with clear thinking.”

- a Patient

Communicating Risk

Our challenge

“I will remember that there is an art to medicine as well as science in that warmth, sympathy and understanding may outweigh the surgeon’s knife or the chemist’s drug”.

-Louis Lasagna, Academic Dean of the School of Medicine at Tufts University, 1964

“What do you want from the rest of your life?”

“What do you want from the rest of your life?”

The Crucial Question:

Our Responsibility

Reassure and offer hopePut the risk in perspectiveDe-mystify the word ‘Cancer’Provide accurate data (use facts)Help the patient think clearly about the risks and benefitsAvoid exploiting the patient’s fearsPrimum non nocere

Risk Assessment

A Phase III Study of Surveillance Therapy Against Radical Treatment (START) in patients Diagnosed

with Favourable Risk Prostate Cancer

NCIC CTG Protocol Number: PR.11SWOG/ECOG/CALGB/RTOG/UKCCR

Study to open 2Q 2007 (any day now!)

START Trial Schema

Randomize(within 6 months of

initial diagnosis)

ARM 1:Radical intervention (radical prostatectomy or radiotherapy based on patient and physician preference)

ARM 2:Active surveillance with radical intervention for either

• Biochemical progression• Grade progression• Clinical progression

Prostate cancer death

Points 0 10 20 30 40 50 60 70 80 90 100

Preop PSA0.1 0.2 0.3 0.5 0.7 1 2 3 4 6 8 100

Gleason Sum5 7 9

4 6 8 10

Extraprostatic Ext.None Focal

Inv.Capsule Established

Surgical MarginsNeg

Pos

Seminal Ves. InvasionNo

Yes

Lymph NodesNeg

Pos

Total Points 0 40 80 120 160 200 240 280

84-Month Rec. Free Prob.0.010.10.30.50.70.80.90.950.980.99

Serial Biopsy Bank

Natural HistoryData Base

Validation ofNomograms

BiomarkerDiscovery

Serum Bank

CorrelativeSciences

STARTTrial

Global Study2100 pts

Thank You